T cell acute lymphoblastic leukemia (T-ALL) is a very malignant disease with few effective treatments. A majority of T-ALL cases are associated with an aberrant expression of the TAL1/SCL gene, which encodes two basic helix-loop-helix (bHLH) proteins capable of forming heterodimers with other bHLH E proteins such as E2A and HEB. Evidence accumulated by our laboratory and others have established that TAL1/SCL proteins act as inhibitors of E proteins, which are both tumor suppressors and regulators of lymphocyte development. Transgenic mice expressing TAL1/SCL develop T cell lymphoma in a similar manner as E2A deficient mice or transgenic mice carrying the Id1 gene, which encodes a dominant-negative inhibitor of E proteins. Therefore, in this renewal proposal, we focus our effort on understanding the mechanisms of T cell lymphomagenesis due to loss of E protein function. We will first ask if the developmental stage at which E protein function is inhibited is crucial for lymphomagenesis. We will also ask if other oncogenic factors such as activated Notch receptors act by interfering with E protein function. We will then test the hypothesis that hyper-responsiveness to pre-T cell receptor or T cell receptor signaling resulting from loss of E protein function combines with secondary mutations of anti-apoptotic genes to promote tumorigenesis. Finally, we will use retroviral insertional mutagenesis to search for additional factors capable of facilitating leukemogenesis in TAL1/SCL or Id1 transgenic mice. Findings from these studies will advance our knowledge regarding the roles of E proteins in T cell development and tumor suppression, with the goal of providing the basis for effective therapies against T-ALL.